Tissue augmentation such as soft tissue augmentation has been used for the purposes of medicine and beauty care. Such an augmentation may be performed by a surgical method via plastic surgery or a non-surgical method to augment the volume of soft tissue by administering a biocompatible material. For example, as a medical purpose it may be used for facial lipoatrophy shown in HIV-positive patients. Facial lipoatrophy refers to loss of subcutaneous fat in the temple and cheeks, and a very thin appearance. In addition, as a beauty care purpose, it has been used for enlarging the volume of the cheek, lip, breast and hip, and reducing fine and deep wrinkles of the skin.
Hyaluronic acid is a biopolymer wherein repeating units consisting of N-acetyl-D-glucosamine and D-glucuronic acid are linearly linked, and is rich in vitreous humor of the eyeball, synovial fluid of joints, chicken combs and the like. Due to excellent biocompatibility, it has been widely used in the medical and medical instrument fields such as ophthalmic surgical aid, joint function improver, drug delivery material, instillations, wrinkle improver and the like, or in the cosmetics field. However, because hyaluronic acid itself has a short half-life of only a few hours after being administered to the human body to render its application limited, there have been studies to increase the half-life (in vivo persistence) by cross-linking. For example, several documents have reported the synthesis of cross-linked hyaluronic acid derivatives in which compounds having two (2) functional groups such as divinyl sulfone, bis-epoxide, bis-halide, formaldehyde and the like are used as a cross-linking agent, and various products based on such preparation methods are commercially available as a dermal filler for skin soft tissue augmentation. U.S. Pat. No. 4,582,865 discloses a cross-linked hyaluronic acid derivative in which divinyl sulfone (DVS) is used as a cross-linking agent, and a hydrogel form thereof is commercially available under the trademark of Hylaform®. U.S. Pat. No. 5,827,937 discloses a process for preparing a cross-linked hyaluronic acid derivative in which multifunctional epoxy compounds are used as a cross-linking agent. Among them, Restylane®, which is a hydrogel formulation of cross-linked hyaluronic acid prepared by using 1,4-butandiol diglycidyl ether (BDDE) as a cross-linking agent of a multifunctional epoxy compound, received approval from the US FDA and is commercially available globally as a dermal filler for tissue augmentation. All of those products are prepared by linking between the hydroxy group of hyaluronic acid and a cross-linking agent. Although the in vivo persistence of those products is increased as compared with uncross-linked hyaluronic acid, there is a problem in in vivo persistence—the fact that they still degrade within six (6) months.
To resolve the problem of low in vivo persistence of commercially available products, the present applicant filed Korean Patent Application No. 10-2008-0074260 which is directed to a method for preparing a hyaluronic acid-adipic acid dihydrazide (ADH) cross-linked product having high in vivo persistence by using ADH—which is linked to the carboxyl group of hyaluronic acid—as a cross-linking agent, based on the conception that the recognition site of a hyaluronic acid-degrading enzyme is the carboxyl group of hyaluronic acid. Meanwhile, the hyaluronic acid-ADH cross-linked hydrogel shows remarkably high in vivo persistence as compared with commercially available cross-linked hyaluronic acid hydrogels, but there have been problems such as the fact that it is easily broken due to low viscoelasticity, is not well swelled and is not easy to perform tissue correction due to uneven distribution in the tissue. In addition, because hyaluronic acid cross-linked products are prepared by using chemicals—which can be recognized as a foreign substance in the body—as a cross-linking agent, there may a problem wherein immune response is caused by a residual cross-linking agent in case of degrading after being administered to the body. As a result, the amount of cross-linking agent or additive, which can act as a foreign substance, should be minimized in the preparation process. Besides, because it is administered to the body, sterilization should be possible, and physicochemical properties such as viscoelasticity needed for tissue correction should be maintained after sterilization.
As explained above, there is a strong demand for cross-linked hyaluronic acid hydrogel—which has good in vivo persistence and biocompatibility, shows good physical properties such as viscoelasticity and the like even after sterilization, and can be administered to the body tissue by being easily charged into a syringe—to be used as an excellent filler for tissue correction.